Elimination of GD3 synthase improves memory and reduces amyloid-beta plaque load in transgenic mice.

Bernardo A, Harrison FE, McCord M, Zhao J, Bruchey A, Davies SS, Jackson Roberts L, Mathews PM, Matsuoka Y, Ariga T, Yu RK, Thompson R, McDonald MP
Neurobiol Aging. 2009 30 (11): 1777-91

PMID: 18258340 · DOI:10.1016/j.neurobiolaging.2007.12.022

Gangliosides have been shown to be necessary for beta-amyloid (Abeta) binding and aggregation. GD3 synthase (GD3S) is responsible for biosynthesis of the b- and c-series gangliosides, including two of the four major brain gangliosides. We examined Abeta-ganglioside interactions in neural tissue from mice lacking the gene coding for GD3S (St8sia1), and in a double-transgenic (APP/PSEN1) mouse model of Alzheimer's disease cross-bred with GD3S-/- mice. In primary neurons and astrocytes lacking GD3S, Abeta-induced cell death and Abeta aggregation were inhibited. Like GD3S-/- and APP/PSEN1 double-transgenic mice, APP/PSEN1/GD3S-/- "triple-mutant" mice are indistinguishable from wild-type mice on casual examination. APP/PSEN1 double-transgenics exhibit robust impairments on a number of reference-memory tasks. In contrast, APP/PSEN1/GD3S-/- triple-mutant mice performed as well as wild-type control and GD3S-/- mice. Consistent with the behavioral improvements, both aggregated and unaggregated Abeta and associated neuropathology were almost completely eliminated in triple-mutant mice. These results suggest that GD3 synthase may be a novel therapeutic target to combat the cognitive deficits, amyloid plaque formation, and neurodegeneration that afflict Alzheimer's patients.

MeSH Terms (22)

Alzheimer Disease Amyloid Amyloid beta-Protein Precursor Animals CD11b Antigen Cells, Cultured Cerebral Cortex Disease Models, Animal Gas Chromatography-Mass Spectrometry Humans Lipid Peroxidation Maze Learning Memory Memory Disorders Mice Mice, Transgenic Mutation Neurons Plaque, Amyloid Presenilin-1 Protein Binding Sialyltransferases

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